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Site-Specific Drug-Releasing Polypeptide Nanocarriers Based on Dual-pH Response for Enhanced Therapeutic Efficacy against Drug-Resistant Tumors.

Dong Y, Yang J, Liu H, Wang T, Tang S, Zhang J, Zhang X - Theranostics (2015)

Bottom Line: To enhance effective drug accumulation in drug-resistant tumors, a site-specific drug-releasing polypeptide system (PEG-Phis/Pasp-DOX/CA4) was exploited in response to tumor extracellular and intracellular pH.This system could firstly release the embedded tumor vascular inhibitor (CA4) to transiently 'normalize' vasculature and facilitate drug internalization to tumors efficiently, and then initiate the secondary pH-response to set the conjugated active anticancer drug (DOX) free in tumor cells.The encapsulated system (PEG-Phis/DOX/CA4), both CA4 and DOX embedding in the nanoparticles, was used as a control.

View Article: PubMed Central - PubMed

Affiliation: 1. National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China ; 2. College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding, 071002, China.

ABSTRACT
To enhance effective drug accumulation in drug-resistant tumors, a site-specific drug-releasing polypeptide system (PEG-Phis/Pasp-DOX/CA4) was exploited in response to tumor extracellular and intracellular pH. This system could firstly release the embedded tumor vascular inhibitor (CA4) to transiently 'normalize' vasculature and facilitate drug internalization to tumors efficiently, and then initiate the secondary pH-response to set the conjugated active anticancer drug (DOX) free in tumor cells. The encapsulated system (PEG-Phis/DOX/CA4), both CA4 and DOX embedding in the nanoparticles, was used as a control. Comparing with PEG-Phis/DOX/CA4, PEG-Phis/Pasp-DOX/CA4 exhibited enhanced cytotoxicity against DOX-sensitive and DOX-resistant cells (MCF-7 and MCF-7/ADR). Moreover, PEG-Phis/Pasp-DOX/CA4 resulted in enhanced therapeutic efficacy in drug-resistant tumors with reduced toxicity. These results suggested that this site-specific drug-releasing system could be exploited as a promising treatment for cancers with repeated administration.

No MeSH data available.


Related in: MedlinePlus

(A) Illustration of the structures of PEG-Phis and Pasp-DOX, and the pH-sensitive hydrazone linker is shown in the black rectangle, which is marked in Pasp-DOX. (B) The preparation of PEG-Phis/Pasp-DOX/CA4 nanoparticles and the pH-responsive process: (1) self-assembly at pH 7.4; (2) protonation and swelling in tumor vessels at pH 7.0-6.0; (3) further swelling in tumor cells at pH 6.0-5.0; (4) demicellization. (C) Schematic interpretation of the system (PEG-Phis/Pasp-DOX/CA4) transporting from tumor vessels into tumor cells and the hypothetic drugs releasing process: (a) swelling in response to tumor extracellular pH and release of CA4; (b) cellular internalization; (c) further swelling in early endosomes; (d) demicellization and triggered the secondary pH response to release of DOX in late endosomes/lysosomes; (e) endosomal escape and release of DOX to nucleus.
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Figure 1: (A) Illustration of the structures of PEG-Phis and Pasp-DOX, and the pH-sensitive hydrazone linker is shown in the black rectangle, which is marked in Pasp-DOX. (B) The preparation of PEG-Phis/Pasp-DOX/CA4 nanoparticles and the pH-responsive process: (1) self-assembly at pH 7.4; (2) protonation and swelling in tumor vessels at pH 7.0-6.0; (3) further swelling in tumor cells at pH 6.0-5.0; (4) demicellization. (C) Schematic interpretation of the system (PEG-Phis/Pasp-DOX/CA4) transporting from tumor vessels into tumor cells and the hypothetic drugs releasing process: (a) swelling in response to tumor extracellular pH and release of CA4; (b) cellular internalization; (c) further swelling in early endosomes; (d) demicellization and triggered the secondary pH response to release of DOX in late endosomes/lysosomes; (e) endosomal escape and release of DOX to nucleus.

Mentions: To address this challenge, it is crucial to fabricate a rational site-specific drug-releasing delivery system, which could not only unload the tumor vascular inhibitor specifically in the tumor vessels to temporarily 'normalize' the tumor vasculature to facilitate drug delivery, but also trigger in the tumor cells to increase effective drug concentration in drug-resistant tumor cells. With this concept, firstly, combretastatin A4 (CA4), one of the most potent antivascular agents 12, was used in our system. CA4 could rapidly inhibit the growth of vasculature in tumors by disrupting the cytoskeletal structures 12. Doxorubicin (DOX), commonly used in the treatment of wide ranges of cancers, was chosen as anticancer drugs 13. It could kill the tumor cells by intercalating into DNA. Hence, combination delivery of these two drugs should elicit synergistic effect in antitumor activity. Secondly, to realize the site-specific release, a smart dual-pH sensitive delivery system was designed to release CA4 and DOX in tumor vasculature and tumor cells, respectively. To construct our system, a biocompatible poly(ethylene glycol)-polyhistidine (PEG-Phis) polypeptide was chosen as the drug carrier (Figure 1A) since the imidazole groups of the polyhistidine block could be protonated at acidic condition 14. The polyhistidine block could transform from hydrophobicity to hydrophilicity by protonation in response to the tumor intracellular pH. Then, DOX was conjugated with polyaspartate (Pasp) by a pH-triggered hydrazone bond to form an inert macromolecular prodrug (Pasp-DOX) 15. The special linker could be broken at pH 5-6 16, which was sensitive to the environment in tumor cells. The pH-triggered macromolecular prodrug Pasp-DOX and the small molecular inhibitor CA4 were encapsulated in the pH-sensitive PEG-Phis to construct the two-stage site-specific releasing system (Figure 1B).


Site-Specific Drug-Releasing Polypeptide Nanocarriers Based on Dual-pH Response for Enhanced Therapeutic Efficacy against Drug-Resistant Tumors.

Dong Y, Yang J, Liu H, Wang T, Tang S, Zhang J, Zhang X - Theranostics (2015)

(A) Illustration of the structures of PEG-Phis and Pasp-DOX, and the pH-sensitive hydrazone linker is shown in the black rectangle, which is marked in Pasp-DOX. (B) The preparation of PEG-Phis/Pasp-DOX/CA4 nanoparticles and the pH-responsive process: (1) self-assembly at pH 7.4; (2) protonation and swelling in tumor vessels at pH 7.0-6.0; (3) further swelling in tumor cells at pH 6.0-5.0; (4) demicellization. (C) Schematic interpretation of the system (PEG-Phis/Pasp-DOX/CA4) transporting from tumor vessels into tumor cells and the hypothetic drugs releasing process: (a) swelling in response to tumor extracellular pH and release of CA4; (b) cellular internalization; (c) further swelling in early endosomes; (d) demicellization and triggered the secondary pH response to release of DOX in late endosomes/lysosomes; (e) endosomal escape and release of DOX to nucleus.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4440445&req=5

Figure 1: (A) Illustration of the structures of PEG-Phis and Pasp-DOX, and the pH-sensitive hydrazone linker is shown in the black rectangle, which is marked in Pasp-DOX. (B) The preparation of PEG-Phis/Pasp-DOX/CA4 nanoparticles and the pH-responsive process: (1) self-assembly at pH 7.4; (2) protonation and swelling in tumor vessels at pH 7.0-6.0; (3) further swelling in tumor cells at pH 6.0-5.0; (4) demicellization. (C) Schematic interpretation of the system (PEG-Phis/Pasp-DOX/CA4) transporting from tumor vessels into tumor cells and the hypothetic drugs releasing process: (a) swelling in response to tumor extracellular pH and release of CA4; (b) cellular internalization; (c) further swelling in early endosomes; (d) demicellization and triggered the secondary pH response to release of DOX in late endosomes/lysosomes; (e) endosomal escape and release of DOX to nucleus.
Mentions: To address this challenge, it is crucial to fabricate a rational site-specific drug-releasing delivery system, which could not only unload the tumor vascular inhibitor specifically in the tumor vessels to temporarily 'normalize' the tumor vasculature to facilitate drug delivery, but also trigger in the tumor cells to increase effective drug concentration in drug-resistant tumor cells. With this concept, firstly, combretastatin A4 (CA4), one of the most potent antivascular agents 12, was used in our system. CA4 could rapidly inhibit the growth of vasculature in tumors by disrupting the cytoskeletal structures 12. Doxorubicin (DOX), commonly used in the treatment of wide ranges of cancers, was chosen as anticancer drugs 13. It could kill the tumor cells by intercalating into DNA. Hence, combination delivery of these two drugs should elicit synergistic effect in antitumor activity. Secondly, to realize the site-specific release, a smart dual-pH sensitive delivery system was designed to release CA4 and DOX in tumor vasculature and tumor cells, respectively. To construct our system, a biocompatible poly(ethylene glycol)-polyhistidine (PEG-Phis) polypeptide was chosen as the drug carrier (Figure 1A) since the imidazole groups of the polyhistidine block could be protonated at acidic condition 14. The polyhistidine block could transform from hydrophobicity to hydrophilicity by protonation in response to the tumor intracellular pH. Then, DOX was conjugated with polyaspartate (Pasp) by a pH-triggered hydrazone bond to form an inert macromolecular prodrug (Pasp-DOX) 15. The special linker could be broken at pH 5-6 16, which was sensitive to the environment in tumor cells. The pH-triggered macromolecular prodrug Pasp-DOX and the small molecular inhibitor CA4 were encapsulated in the pH-sensitive PEG-Phis to construct the two-stage site-specific releasing system (Figure 1B).

Bottom Line: To enhance effective drug accumulation in drug-resistant tumors, a site-specific drug-releasing polypeptide system (PEG-Phis/Pasp-DOX/CA4) was exploited in response to tumor extracellular and intracellular pH.This system could firstly release the embedded tumor vascular inhibitor (CA4) to transiently 'normalize' vasculature and facilitate drug internalization to tumors efficiently, and then initiate the secondary pH-response to set the conjugated active anticancer drug (DOX) free in tumor cells.The encapsulated system (PEG-Phis/DOX/CA4), both CA4 and DOX embedding in the nanoparticles, was used as a control.

View Article: PubMed Central - PubMed

Affiliation: 1. National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China ; 2. College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding, 071002, China.

ABSTRACT
To enhance effective drug accumulation in drug-resistant tumors, a site-specific drug-releasing polypeptide system (PEG-Phis/Pasp-DOX/CA4) was exploited in response to tumor extracellular and intracellular pH. This system could firstly release the embedded tumor vascular inhibitor (CA4) to transiently 'normalize' vasculature and facilitate drug internalization to tumors efficiently, and then initiate the secondary pH-response to set the conjugated active anticancer drug (DOX) free in tumor cells. The encapsulated system (PEG-Phis/DOX/CA4), both CA4 and DOX embedding in the nanoparticles, was used as a control. Comparing with PEG-Phis/DOX/CA4, PEG-Phis/Pasp-DOX/CA4 exhibited enhanced cytotoxicity against DOX-sensitive and DOX-resistant cells (MCF-7 and MCF-7/ADR). Moreover, PEG-Phis/Pasp-DOX/CA4 resulted in enhanced therapeutic efficacy in drug-resistant tumors with reduced toxicity. These results suggested that this site-specific drug-releasing system could be exploited as a promising treatment for cancers with repeated administration.

No MeSH data available.


Related in: MedlinePlus